HER2 overexpression is an adverse prognostic factor characterized by a shorter disease-free period and decreased overall survival.[2–4]

Trastuzumab (T) is a humanized monoclonal antibody, with specificity for HER2 protein, which exhibits antitumor activity in patients with breast cancer.

The results of phase II trials[5,6] indicate that T is active against HER2-overexpressing breast cancer, both in women undergoing first-line treatment, and in those who have previously been treated with chemotherapy for metastatic disease.[7]

The combination of T and chemotherapy was evaluated in preclinical and clinical studies. These studies showed a synergy between a number of anticancer drugs and T when used in combination against cancer cells with HER2 overexpressed,[8–12] and that the increased cytotoxic effects of chemotherapeutic drugs follow a logarithmic curve.[13]

In clinical setting, the addition of T to chemotherapy, in patients with HER2-overexpressing metastatic breast cancer, significantly increased the treatment activity, provided a survival advantage and improved patients quality of life.[14,15] Overall, clinical studies showed that T has changed the natural history of HER2-positive breast cancer, either in the metastatic[16–18] or the adjuvant setting.[19,20]

Vinorelbine (VNR) is a semi-synthetic vinca alkaloid that showed activity and efficacy in breast cancer patients. Its mechanism of action is only partially known, but it is thought to be similar to vinblastine and vincristine, an antimicrotubule agent, in that it arrests cell division in mitosis.[21]

The combination of VNR and T was tested in preclinical studies and appeared to be synergistic against all four HER2-overexpressing cell lines[14] with a reproducible synergism in many preclinical models.[10–12]

In the clinical setting, the combination of T and a weekly administration of VNR appeared to be active and well tolerated.[22–25] Women with HER2-overexpressing metastatic breast cancer, when treated with T and weekly VNR, had a better prognosis than those with HER2-negative disease treated with VNR.[23]

All previous studies administered T, in combination with VNR, as a weekly i.v. infusion. Our group designed a modified combination regimen in order to improve the patients' clinical advantages, acceptance and compliance. The weekly administration of VNR, which forced patients to undergo a weekly hospital admission, was substituted with a d1 and d3 VNR oral administration q3wks. This allowed them to submit to only a single hospital access once every 3 weeks.

Trastuzumab was given with a three-weekly schedule as well, according to recent clinical and pharmacokinetic findings indicating that T could be administered less frequently, at higher individual doses, without compromising efficacy or tolerability.[26]

This schedule of VNR (d1 and 3) is supported by the observation that the plasma concentrations of the drug decrease in a triexponential manner with a terminal phase half-life of about 40 h. Moreover, this schedule appeared to be active and very well tolerated in many phase II studies that we conducted in breast cancer patients, either in metastatic disease or as primary treatment in operable breast cancer.[27–30]

The i.v. administration of VNR, which is burdened by complications such as phlebitis at the site of drug injection or right diaphragmatic supraelevation,[31] was substituted by an oral VNR administration route which eliminates the risk of these side-effects and frees up the nursing staff. Moreover, we recently observed patients' preference for oral chemotherapy[32] which provides a prevailing sense of freedom and reduces the unpleasantness of having to wait in the hospital.

The use of oral VNR is supported by results of many studies which show similar levels of variability in pharmacokinetics between oral and i.v. routes[33] and indicate comparable activity and safety profiles.[25] Moreover, preliminary data support the combination of oral VNR and T, showing it to be feasible and well tolerated.[34,35]

We report the results of a mono-institutional prospective phase II study testing this new treatment schedule, with oral VNR given on d1 and 3 combined with T, given i.v. on d1, repeated every 3 weeks, in patient with HER2-overexpressed metastatic breast cancer. VNR was given at the dose of 55 mg/m2 on d1 and d3 every 3 weeks, this dosage being the equivalent dose of i.v. vinorelbine (i.v.VNR) 22.5 mg/m2. The dose was recommended for further phase II studies in a previous dose-escalation trial that we carried out with oral VNR in combination with capecitabine for patients with metastatic breast cancer.[36]